Abstract The insulin receptor substrate proteins Irs1 and Irs2 mediate insulin/IGF signaling (IIS) throughout the body? including the brain?and mice that lack Irs1 and Irs2 develop insulin resistance and metabolic disease. While substantial evidence exists that peripheral insulin resistance and type 2 diabetes (T2D) exacerbate age-related cognitive decline and ADRD (Alzheimer?s Disease and Related Dementia), ascertaining causation by either impaired central IIS or ?metabolic sequelae? of peripheral metabolic disease requires model systems that can yield mechanistic insights. Above all, experimental systems are required that allow measurement of parameters relevant to human cognitive impairment across a range of well-controlled conditions. Our approach satisfies this imperative through routinized analyses of hippocampal function?including partially hippocampus- dependent spatial learning in the Morris water maze (MWM) and neurogenesis in the dentate gyrus of the hippocampus (DG). These assays are validated by our preliminary studies on mice lacking Irs2 in neurons (nIrs2-/- mice), and extended in our approach to mice with unique central (neuronal) and peripheral (e.g. pancreas or liver) expression of Irs1 and Irs2, plus down-stream Foxo1. We moreover analyze directly central IIS mediated by Irs1 and Irs2 in the hippocampus, together with its possible feedback regulation by multi-site serine/threonine phosphorylation of Irs1 and Irs2 (pS/TIrs). AIM1 tests the possibly unique roles of neuronal Irs1 and Irs2 to mediate central IIS?answering whether the benefits to hippocampal function of attenuated neuronal IIS via Irs2 seen in nIrs2-/- mice owe to compensatory upregulation of neuronal IIS via Irs1. AIMs 2-3 focus on the mechanistic significance of metabolic sequela. Since high blood glucose and compensatory insulin hypersecretion are prominent metabolic sequelae of T2D, AIM2 takes a novel approach to restore Irs2 expression in beta cells (reducing glucose) or liver (reducing glucose and insulin) in diabetic Irs2 knockout mice. AIM3 exploits our established LDKO and LTKO mouse models?which lack hepatic Irs1 and Irs2 (diabetic) or Irs1 and Irs2, plus Foxo1 (non-diabetic). First, AIM 3 compares hippocampal function in LDKO vs LTKO mice created acutely using viral Cre. Second, since our published work supports a role of hepatic FoxO1 and increased liver-secreted hepatokine follistatin (Fst) in propagating hepatic insulin resistance to other tissues, AIM 3 employs viral methods to restore FoxO1 expression in LTKO mice, or to knock down expression of Fst in LDKO mice, investigating in detail the effects on hippocampal function. How insulin resistance and diabetes promote cognitive decline is an important clinical and research question. Together, the proposed experiments can elucidate connections between metabolic disease and cognitive dysfunction by dissecting roles of neuronal Irs1 and Irs2, and determining the specific influences of impaired peripheral insulin sensitivity and associated metabolic sequelae upon hippocampal function.